Transcript

[Music]

Kevin Flanigan: Welcome to this month in muscular dystrophy. I'm Kevin Flanigan from the Center for Gene Therapy at Nationwide Children's Hospital in Columbus, Ohio. Each month on this podcast we invite authors in recent publications to discuss how their work improves our understanding inherited neuro muscular diseases, and what their work might mean for treatment of these diseases.

Today it's my great pleasure to have as our guest Dr. Hugh Allen. Who's a member of our Center for Gene Therapy, Professor of Pediatrics in Medicine at the Ohio State University, and Vice Chairman of the Department of Pediatrics here at Nationwide Children's Hospital.

Hugh, thanks for joining us today.

Hugh Allen: Thank you.

Kevin Flanigan: As our pleasure to discuss a very recent paper, in fact so recent it's only available online. Although I'll remind our listeners that they can find a link to the abstract of the paper on our website. The paper is entitled "Effects of Angiotensin-Converting Enzyme Inhibitors and/or Beta Blockers on the Cardiomyopathy in Duchenne Muscular Dystrophy".

01:07

That's a mouthful. So maybe we'll start with just talking about the term Cardiomyopathy. What is a Cardiomyopathy?

Hugh Allen: Cardiomyopathy is disease of the heart muscle. It can come in many forms. The Cardiomyopathy could be as second heart with all that Hypertrophic Cardiomyopathy. It can be a dilated heart such as what we see in Viral Myocarditis or some genetic defects where the heart is enlarged due to ineffective contraction usually squeezing systolic.

There is restrictive cardiomyopathy which is a stiffened ventricle. Examples would be fat deposition in adults who are extremely obese, or amyloid which is an unusual protein that fills usually adult muscle. There is a non compaction cardiomyopathy where the parts of the muscles are essentially chewed away from some process and all looks like forced of palm front as you look at the ventricle itself and there are mixed forms.

02:16

Kevin Flanigan: So I gather one of the key point to that then is we think of Duchenne Muscular Dystrophy, disease of muscle and the heart is a muscle too, and it's affected by this disorder.

Hugh Allen: That's precisely correct. And the form of cardiomyopathy that we see traditionally has been called dilated. But actually many of these young men do not have a dilated heart due to the scarring or the fibrosis that causes at least some of the areas so have restrictive.

Kevin Flanigan: That's an early change of the current cardiomyopathy. So let's talk a little bit more about cardiomyopathy as part of Duchenne Muscular Dystrophy. So what do we know about it in this disease?

Hugh Allen: We know that it's part and parcel with Duchenne with the various dystrophinopathy, Duchenne, or Becker.

03:06

The heart muscle can be affected at various ages, the mean age of onset that we saw in our paper was about 14-1/2 years. This is consistent with what's found in the literature. But we have some patients as young as seven, some patients as old as 22 with and without cardiomyopathy.

Kevin Flanigan: So quite a lot of variation.

Hugh Allen: Correct.

Kevin Flanigan: But most boys with Duchenne Dystrophy do infect eventually get cardiomyopathy?

Hugh Allen: The famous cardiologist in St. Louis, Charlie Canter says, if you have Duchenne, you have cardiomyopathy.

Kevin Flanigan: I see.

Hugh Allen: So the timing and the definition of cardiomyopathy I think is both in moving target.

Kevin Flanigan: Now it's my impression and maybe you can comment on it, my impression is that maybe we see more other becomes more obvious because we're better taken care of the ventilatory issues for example in boys with Duchenne Dystrophy. Is that true or is that..

04:01

Hugh Allen: I think that's one. This case used to die other lung disease, but now with the improved pulmonary care and the use of BiPAP, it's really filtering out the heart as the culprit.

Kevin Flanigan: So it's certainly becoming something we pay attention to a lot more in clinic and..

Hugh Allen: Right. And we're more aware, I mean, we routinely screen this young gentleman for it because now as we all see in the paper we can offer therapy. In the past, I think it was a largely ignored by present phenomenon.

Kevin Flanigan: And when we talk about cardiomyopathy, I know there's many ways to measure it, but many of the parents who might listen to this hear numbers like the ejection fraction. Can you talk a little bit about that number and what it means for cardiomyopathy?

Hugh Allen: Certainly. We assess the heart generally with echocardiography, but MRI is a really good tool to use as well. The filling of the heart if you think of the left ventricle as a strawberry. When it's filled up that's called diastole.

05:00

And then it ejects or empties a certain portion of that. That portion that's ejected, the fraction that's ejected we call the ejected fraction. So it's the amount out over the amount that started with. And that's right now seems to be the best measure.

Kevin Flanigan: And I know that around 55% is sort of the number that we often think of cardiomyopathy?

Hugh Allen: This goes way back to the Framingham Study where several adults in New England were studied and all was found those who had ejection fractions less than 50% eventually died of cardiomyopath, so that became the definition.

The Muscular Dystrophy Community of Cardiologist has floated that ejection fraction up a bit both in Europe and here in the United States, and most agreed that 55% is at least a flip of the coin number that we choose to define the presence of cardiomyopathy.

06:05

Kevin Flanigan: All right. And I know it's a number that parents do hear that ejection fraction, they might hear their child go on a drug and the number might change over time it might change. And that's key I know when we get to the paper, one of the features of the paper. Well let's talk a little bit about Angiotensin-Converting Enzyme Inhibitors, that's one of the categories of drugs that's used in the study here. What do they do?

Hugh Allen: This is a very effective drug that inhibits enzyme that leads to the blood vessels particularly the arterioles to constrict. That inhibition therefore keeps them from constricting and allows them to relax. The relaxation makes the work at the heartless, the analogy being if you had a cart being pulled up a hill by a horse. Now the cart is full of rocks, ass the heart ages, as the horse ages becomes a sway back.

07:06

He doesn't have the pulling capability. But of we took the rocks out of the cart, his work would be less. So that analogy at least Dr. Brown has offered up as an explanation. ACE inhibitors have an interesting history and actually it goes back to the early '70s when people were working on the renin-angiotensin cycle.

Kevin Flanigan: That's the pathway...

Hugh Allen: That's the pathway as the enzymatic pathway that's used. And a (pit viper) rattle snake in Brazil was biting banana plantation workers and they would just drop of low blood pressure. So a vial of this was taken to Sir John Vane Laboratory at the Royal College of Surgeons in England. And they tried it out on dogs and they suffered the same fate. It took however about 25 years to actually synthesize this into a pill form.

08:03

That became an Enalapril, Captopril and the like. And those were used in adults that changed the whole world of cardiomyopathy who were patients who are on transplant list all of a sudden came off the list and came back to work, had longer life span and it's really a miracle drug. It's also used for treating high blood pressure/hypertension.

Kevin Flanigan: So this is a serendipity this finding from the pit viper?

Hugh Allen: Most experience in nature are what we said we discovered, but it's already laid out for, you just have to look.

Kevin Flanigan: So these drugs, you mentioned a couple of names. Parents probably know them the Lisinopril, Enalapril, Captopril, Monopril this are all drugs that this pril drugs are the ACE inhibitors?

Hugh Allen: Right. And the reason by the way we chose Lisinopril is it's a one dose a day rather than two or three as Captopril or Enalapril are.

09:01

Kevin Flanigan: Well how about Beta Blockers? What are they? What do they do?

Hugh Allen: Beta Blockers basically inhibit the effects of epinephrine or adrenaline, therefore you have a slower hear rate. And we've largely been using it to slow the heart rate down. These guys not only can have a cardiomyopathy, but maybe independently they have disorder automaticity which is a average heart rate over 100 in these teens.

And that's part and parcel of Duchenne. So we have been treating this guys' rapid heart rates with the Beta Blocker to slow it down. They feel much more comfortable when that's used. In the adult world Beta Blocker are used to treat heart failure, again slowing the rate down making the work of the heart more efficient.

Kevin Flanigan: Well that really brings us up to your recent study. Actually I guess whether with 65 boys that you identified, 42 of them will get treated with this drug, these inhibitors. Either with or without the Beta Blockers.

10:04

Tell us what did you find? What was the study? What did you find?

Hugh Allen: Sort of a quick capsule summary is we found it didn't make any difference if they were on either an ACE inhibitor or if a Beta Blocker were added. The effect were good.

Kevin Flanigan: The Beta Blocker?

Hugh Allen: What we saw was an improvement in the ejection fraction in the entire population and it lasted for the study period. Those who had the Beta Blocker added usually for the disorder automaticity or the rapid heart rate really did exactly the same as those on the ACE inhibitor. So the addition of the Beta Blocker that treat failure didn't make any difference but its presence did help the heart rate. So the combination really helped these guys out.

Kevin Flanigan: Tell me how much of a benefit did you find in an average with this medications?

11:03

Hugh Allen: When the ACE inhibitor population was started the mean ejection fraction with a lot of variability was under 50%, -47%. And it went up to nearly normal at 52% with the population and the ACE plus Beta Blocker who were about two years older, and a little bit lower ejection fraction not significantly lower 46% they went up to 50%. But several really sailed up into the 60% range and held there. So it's quite effective.

Kevin Flanigan: So this is an interesting study, certainly confirmed early reports and showed the Beta Blocker addition was no way harmful and certainly helpful for some.

Hugh Allen: Actually this study has an advantage and there was a prospectively evaluated population using the same parameters. We have a database of everyone of the Duchenne boys that we've ever seen. And by keeping that database and serially looking at them, we can offer this information which we thought was there before, but disconfirmed.

12:07

Kevin Flanigan: What are some of the outstanding questions that remain for Duchenne and cardiomyopathy?

Hugh Allen: I think the first important question is, what is cardiomyopathy and Duchenne? Is it when a boy is born, he has cardiomyopathy or is it something that's an ejection fraction of 55%? The truth probably is it's somewhere in between. MRI study by HOR and Cincinnati showed that even at age 10, many of these boys had some fiber deposition scarring in the myocardium.

So subtle change and the way the fibers contracted circumferential fiber shortening that they could measure by MRI and actually predicts probably an early onset all those sub clinical.

13:03

The question of prophylactic therapy is always out there. Should these boys be treated, the answer is not in. We don't know. There's a lot of this hardcore feeling both ways. I'd like to get away from feeling and get data, and see in a carefully designed double blind controlled study. Is it beneficial to put these guys on treatment early or not?

We do have information from Europe, but really there are ejection fractions on treatment or not on treatment the two groups came out exactly the same. There were more deaths in the non early treated group, but we don't know why they died. I think that is provocative I think that the horse study is provocative, but it certainly opens the gates for a careful pre-ejection fraction 55% type study.

14:01

Kevin Flanigan: Well Hugh, any final comments about the study?

Hugh Allen: I'd like to give credit where it's due. And that is without MDA support the study could not have been accomplished. That our senior fellow on cardiology Dr. Phil Trush and her post doc., Dr. Laurence Villet along with you and Jerry Mendell were instrumental in getting this thing put together.

Kevin Flanigan: Well thanks once again for taking the time to explain this very interesting study to us today.

Hugh Allen: Oh thank you for the opportunity.

Kevin Flanigan: This podcast is brought to you by Nationwide Children's Hospital and by the Nationwide Children's Senator Paul Wellstone Muscular Dystrophy Cooperative Research Center. You can find out more about the Muscular Dystrophy program and ongoing clinical trials at Nationwide Children's at our website Nationwidechildren's.org/muscular-dystrophy-podcast. You'll also find a link to the published abstract of the study that we've discussed today.

15:01

Thank you for joining us ad we'll look forward to talking to you next month.